Nature Medicine Contents: November 2013 Volume 19 Number 11 pp 1351-1546

TABLE OF CONTENTS November 2013 Volume 19, Issue 11 Podcast Focus Editorial News Book Review News and Views Community Corner Research Highlights Perspective Reviews Brief Communications Articles Letters Technical Reports Advertisement Roche's X-tremeGENE Transfection Reagents Efficiently transfect difficult cells, including more than 100 cancer cell lines. Free sample and protocols at www.x-tremegene.roche.com For life science research only. Not for use in diagnostic procedures. Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Nature Medicine and Eli Lilly and Company present: Shifting Paradigms on Alzheimer's Disease December 3, 2013 Lilly Corporate Center, Indianapolis, IN, USA  Click here to register for this symposium today!     Nature Medicine Podcast  Top Hedging on hedgehog Hedgehog inhibitors show promise in combination therapy for brain cancer and as new way to treat a bone condition called heterotopic ossification. Listen Now Editorial Top License with care   p1351 doi:10.1038/nm.3399 University technology transfer offices are tasked with helping bring the inventions made by academics to the attention of potential investors. But selling off intellectual property to patent aggregators in an effort to bring in money to their institutions could stifle the future development of new technologies. News Top Sun sets on protein initiative, casting shadow over drug discovery   p1352 Elizabeth Devitt doi:10.1038/nm1113-1352 Trial designs advance to overcome bitter pill of placebo effect   p1353 Monica Heger doi:10.1038/nm1113-1353 Pharmacogenetic tests yield bonus benefit: better drug adherence   pp1354 - 1355 Elie Dolgin doi:10.1038/nm1113-1354 Small nanobody drugs win big backing from pharma   pp1355 - 1356 Sarah CP Williams doi:10.1038/nm1113-1355 Cancer immunotherapy advances spawn calls for new endpoints   p1357 Elie Dolgin doi:10.1038/nm1113-1357 News in Brief Biomedical briefing   pp1358 - 1359 doi:10.1038/nm1113-1358 Q&A Straight talk with...Ricardo Dolmetsch   p1360 doi:10.1038/nm1113-1360 In August, Novartis appointed Ricardo Dolmetsch to be the company's global head of neurosciences[mdash]the first new hire for its reincarnated neuroscience division. As a professor at California's Stanford University School of Medicine for the past ten years, Dolmetsch made his name using induced pluripotent stem (iPS) cells to study a rare form of autism known as Timothy syndrome. Elie Dolgin met with Dolmetsch at the Novartis Institutes for BioMedical Research in the Technology Square area of Cambridge to discuss how he plans to succeed where so many others have failed. News Feature Telltale hearts   pp1361 - 1364 Jeanne Erdmann doi:10.1038/nm1113-1361 Each year, tens of thousands of young people worldwide die suddenly after their hearts stop beating for no apparent reason. Genetic testing for inherited heart rhythm disorders can potentially offer grief-stricken family members an explanation for the loss of their loved ones and provide actionable diagnostic information to help them avoid the same fate. And yet, such 'molecular autopsies' are rarely performed by the forensic experts who investigate unexplained deaths. Jeanne Erdmann meets the medical professionals who are trying to change that. Opinion A new value proposition   p1365 Michael Kolodziej, Ira Klein and Lonny Reisman doi:10.1038/nm1113-1365 Better outcomes and lower costs are needed in cancer care. To establish true value for money, researchers must establish what matters most to patients and other relevant stakeholders[mdash]including families, employers and even insurance companies. Book Review Top Eugenics to medical genetics   p1366 Wylie Burke reviews The Science of Human Perfection: How Genes Became the Heart of American Medicine by Nathaniel Comfort doi:10.1038/nm.3315 News and Views Top Mst-1 switches between cardiac cell life and death   pp1367 - 1368 Rimpy Dhingra and Lorrie A Kirshenbaum doi:10.1038/nm.3371 Autophagy and apoptosis are ancient processes that regulate cell fate under normal and disease conditions. A new study in mice identifies mammalian Ste20-like kinase-1 (Mst-1) as a missing link that interfaces between these pathways for cell survival and death during cardiac stress (pages 1478-1488). See also: Article by Maejima et al. An endogenous factor mediates shock-induced injury   pp1368 - 1369 Peter A Ward doi:10.1038/nm.3387 An endogenous molecule secreted by macrophages during stress is a new mediator for the wave of inflammation triggered during hemorrhagic and septic shock. This finding suggests a potential drug target to reduce organ injury and death after shock (pages 1489-1495). See also: Article by Qiang et al. Striking a balance in fragile X   pp1370 - 1371 Laura N Smith and Christopher W Cowan doi:10.1038/nm.3383 In fragile X syndrome, the absence of fragile X mental retardation protein (FMRP) allows the production of certain proteins to go unchecked in the brain. A recent study in mice suggests that bringing excessive translation into balance may provide a key to treating this syndrome (pages 1473-1477). Sirt1-Claudin-1 crosstalk regulates renal function   pp1371 - 1372 Deepak Nihalani and Katalin Susztak doi:10.1038/nm.3386 Understanding the molecular mechanisms that govern diabetes-induced loss of kidney function is crucial. A new study shows that in mouse models of diabetes, sirtuin 1 (Sirt1) in the proximal tubules of the kidney can modulate the expression of podocyte Claudin-1, a key regulator of albuminuria and glomerular function (pages 1496-1504). See also: Article by Hasegawa et al. Nature Medicine JOBS of the week Post-Doctoral Fellow University of Michigan Postdoctoral Scientist University of Oxford Postdoctoral fellowship Regional Blood Center de Ribeir�o Preto Postdoctoral position University Hospital Zurich More Science jobs from Nature Medicine EVENT Clinical Genomics 2014 28.01.14 Boston, USA More science events from Community Corner Top Slimming down via the microbiota   pp1374 - 1375 doi:10.1038/nm.3398 Research Highlights Top Neurodevelopmental disorders: Microcephaly mutations | Cancer: Liver cancer progenitors | Stem cells: A reprogrammable rodent | Immunology: Mucous-mediated tolerance Focus on targeted cancer therapies Editorial Top Keeping pace with cancer   p1380 doi:10.1038/nm.3395 Perspective Top Mechanisms of resistance to therapies targeting BRCA-mutant cancers   pp1381 - 1388 Christopher J Lord and Alan Ashworth doi:10.1038/nm.3369 Synthetic lethality describes a situation in which defects in either one of two genes are not detrimental, but combining defects in the two genes is lethal. The targeting of BRCA-deficient tumors by PARP inhibitors is the first clinical example utilizing the principle of synthetic lethality to treat cancer. Despite the promise of this approach, a number of resistance mechanisms have been identified, and this Perspective describes these mechanisms and their clinical relevance. Reviews Top The quest to overcome resistance to EGFR-targeted therapies in cancer   pp1389 - 1400 Curtis R Chong and Pasi A Janne doi:10.1038/nm.3388 Despite the initial promise of cancer therapies targeted against the epidermal growth factor receptor (EGFR), tumors treated with these agents eventually develop resistance. In this Review, the authors outline the complex mechanisms by which tumors become resistant to EGFR-targeted drugs and antibodies and offer insights into new strategies that might be employed to circumvent therapeutic resistance. Tumor adaptation and resistance to RAF inhibitors   pp1401 - 1409 Piro Lito, Neal Rosen and David B Solit doi:10.1038/nm.3392 Inhibitors of RAF kinase have shown substantial benefits in the clinic for the treatment of people with BRAF-mutant melanoma, but their utility is limited by the emergence of therapeutic resistance. In this Review, the authors provide a synthesis of the currently known mechanisms of resistance to RAF-targeted therapies and show how their model has implications for the development of more effective strategies to treat patients with BRAF-mutant tumors. Unraveling the therapeutic potential of the Hedgehog pathway in cancer   pp1410 - 1422 Dereck Amakye, Zainab Jagani and Marion Dorsch doi:10.1038/nm.3389 There has been substantial progress in understanding the role of Hedgehog (Hh) signaling in cancer in recent years, as exemplified by the approval by the US Food and Drug Administration of the Hh pathway inhibitor vismodegib in 2012 for the treatment of basal cell carcinoma. This Review outlines these advances and charts the development of Hh inhibitors, providing a critical overview of how these drugs have fared in the clinic. Microenvironmental regulation of tumor progression and metastasis   pp1423 - 1437 Daniela F Quail and Johanna A Joyce doi:10.1038/nm.3394 Cancer cells can alter and build a permissive microenvironment that supports the malignant behavior of a growing primary tumor and developing metastases. But the role of the players in the stroma is rather complex, and their functions are intertwined, requiring a strategy to normalize the microenvironment to halt cancer progression. Re-education of stromal cells that interact with tumor cells may be a promising therapeutic avenue to exploit a genetically stable part of the tumor. The epigenetics of epithelial-mesenchymal plasticity in cancer   pp1438 - 1449 Wai Leong Tam and Robert A Weinberg doi:10.1038/nm.3336 Epithelial-mesenchymal transitions (EMTs) are a key requirement for cancer cells to metastasize and colonize in a new environment. Epithelial-mesenchymal plasticity is mediated by master transcription factors and is also subject to complex epigenetic regulation. This Review outlines our current understanding of the interactions between EMT-inducing transcription factors and epigenetic modulators during cancer progression and the therapeutic implications of exploiting this intricate regulatory process. Tumor metastasis: moving new biological insights into the clinic   pp1450 - 1464 Liling Wan, Klaus Pantel and Yibin Kang doi:10.1038/nm.3391 Increasing understanding of how tumor cells metastasize, what secondary organs are the targets of disseminating tumor cells and what molecular mechanisms are involved in the metastatic cascade can provide a road map to translate new biological insights into clinical practice. As tumor metastasis remains the main cause of death for patients with cancer, this is an unmet clinical need that requires a thorough examination of the most recent and relevant translational research. Brief Communications Top Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer   pp1469 - 1472 Aria Vaishnavi, Marzia Capelletti, Anh T Le, Severine Kako, Mohit Butaney et al. doi:10.1038/nm.3352 The authors employ targeted next-generation sequencing to identify driving oncogenic alterations in patients with lung cancer with no known oncogenes. They discover two gene fusions involving NTRK1 that lead to constitutive activation of the kinase TRKA and can drive transformation. The fusions can be targeted with available kinase inhibitors and may represent therapeutic targets. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology   pp1473 - 1477 Tsuyoshi Udagawa, Natalie G Farny, Mira Jakovcevski, Hanoch Kaphzan, Juan Marcos Alarcon et al. doi:10.1038/nm.3353 Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of the translational repressor protein FMRP. Now, Joel D. Richter and his colleagues report that knocking down the expression of the translational activator protein CPEB can restore normal levels of translation and rescue behavioral deficits in a mouse model of FXS. See also: News and Views by Smith & Cowan Articles Top Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2   pp1478 - 1488 Yasuhiro Maejima, Shiori Kyoi, Peiyong Zhai, Tong Liu, Hong Li et al. doi:10.1038/nm.3322 The kinase Mst1, which acts in the Hippo pathway, controls cell proliferation, differentiation and apoptosis. Junichi Sadoshima and his colleagues show that Mst1 in cardiomyocytes phosphorylates the protein Beclin1 to coordinately suppress autophagy and promote apoptosis, thereby having deleterious effects on the heart. See also: News and Views by Dhingra & Kirshenbaum Cold-inducible RNA-binding protein (CIRP) triggers inflammatory responses in hemorrhagic shock and sepsis   pp1489 - 1495 Xiaoling Qiang, Weng-Lang Yang, Rongqian Wu, Mian Zhou, Asha Jacob et al. doi:10.1038/nm.3368 Cellular stress results in the release of damage-associated molecular pattern (DAMP) molecules that promote inflammatory responses. Here Ping Wang and colleagues show that cold-inducible RNA-binding protein (CIRP) is a DAMP that is released into the circulation in response to hemorrhagic shock and sepsis. It promotes proinflammatory cytokine release by binding to the TLR4-MD2 complex. Blockade of CIRP reduces inflammation, organ injury and mortality in animal models of hemorrhage and sepsis, suggesting that CIRP may be targeted therapeutically in these conditions. See also: News and Views by Ward Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes   pp1496 - 1504 Kazuhiro Hasegawa, Shu Wakino, Petra Simic, Yusuke Sakamaki, Hitoshi Minakuchi et al. doi:10.1038/nm.3363 Diabetic nephropathy is the most common cause of end-stage renal disease. Shu Wakino and colleagues now show that high-glucose conditions in the renal proximal tubules result in downregulation of Sirt1 expression there and in the glomeruli, resulting in epigentic upregulation of Claudin-1 in the glomeruli and thus proteinuria. They also show that genetic or chemical targeting of Sirt1 in the kidney is sufficient to improve kidney function in a mouse model of diabetic nephropathy. See also: Article by Qiang et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification   pp1505 - 1512 Jean B Regard, Deepti Malhotra, Jelena Gvozdenovic-Jeremic, Michelle Josey, Min Chen et al. doi:10.1038/nm.3314 In a new study, Yingzi Yang and her colleagues show that a careful balance between Wnt and Hedgehog signaling is required to maintain proper differentiation of osteogenic precursor cells. Upon mutation of GNAS, this balance is disturbed and severe bone disease develops, including either heterotopic ossification or fibrous dysplasia. Letters Top Differential regulation of myeloid leukemias by the bone marrow microenvironment   pp1513 - 1517 Daniela S Krause, Keertik Fulzele, Andre Catic, Chia Chi Sun, David Dombkowski et al. doi:10.1038/nm.3364 Alteration of the bone marrow microenvironment by activation of the parathyroid hormone receptor attenuates chronic myelogenous leukemia (CML) but enhances acute myeloid leukemia (AML) in mouse models, suggesting that the leukemia stem-cell niches in CML and AML are distinct. Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities   pp1518 - 1523 Mariella Gruber Filbin, Sukriti K Dabral, Maria F Pazyra-Murphy, Shakti Ramkissoon, Andrew L Kung et al. doi:10.1038/nm.3328 This study identifies the concurrent activation of SHH and PI3K signaling by loss of PTEN as a frequent event in glioblastoma tumors that can be targeted with combination treatments using approved drugs to achieve antitumor responses in vivo. The results could potentially lead to the exploration of much needed new combination therapies for human brain tumors. Chloride extrusion enhancers as novel therapeutics for neurological diseases   pp1524 - 1528 Martin Gagnon, Marc J Bergeron, Guillaume Lavertu, Annie Castonguay, Sasmita Tripathy et al. doi:10.1038/nm.3356 Dysfunction of the potassium-chloride cotransporter KCC2 has been linked to many neurological diseases, including pain, anxiety and epilepsy. Now, Yves De Koninck and his colleagues report that they have developed a novel small-molecule compound that is orally bioavailable and can activate KCC2 and reduce chronic pain in rats. Loss of immune escape mutations during persistent HCV infection in pregnancy enhances replication of vertically transmitted viruses   pp1529 - 1533 Jonathan R Honegger, Seungtaek Kim, Aryn A Price, Jennifer A Kohout, Kevin L McKnight et al. doi:10.1038/nm.3351 Here, Honegger et al. study two HCV-infected women through two consecutive pregnancies and chronicle T cell escape mutations in viral proteins that revert during pregnancy and reappear postpartum. The findings highlight the dynamic between T cell-mediated pressure and viral fitness, with implications for vertical transmission of HCV. Technical Reports Top High-throughput identification of antigen-specific TCRs by TCR gene capture   pp1534 - 1541 Carsten Linnemann, Bianca Heemskerk, Pia Kvistborg, Roelof J C Kluin, Dmitriy A Bolotin et al. doi:10.1038/nm.3359 The lack of robust and high-throughput technologies to analyze the human TCR repertoire has been a bottleneck in the analysis of human T cell responses. Linnemann and colleagues have addressed this issue by using a TCR gene capture technology that, because of its quantitative nature, allows the rapid identification of TCRab pairs from bulk populations of cells without the need for single-cell cloning. Such an approach should be useful in obtaining defined antigen-reactive TCRs for therapeutic purposes. A new cloning and expression system yields and validates TCRs from blood lymphocytes of patients with cancer within 10 days   pp1542 - 1546 Eiji Kobayashi, Eishiro Mizukoshi, Hiroyuki Kishi, Tatsuhiko Ozawa, Hiroshi Hamana et al. doi:10.1038/nm.3358 Progress in T cell receptor (TCR) gene therapy has been hampered by the lack of a rapid and efficient screening system for antigen-specific TCRs. Here, Kobayashi et al. have developed a direct single-cell TCR cloning system for cloning antigen-specific TCRs from peripheral blood in 10 d. The approach is used to clone and analyze Epstein-Barr virus-specific TCRs from healthy donors with latent Epstein-Barr virus infection, as well as TCRs from peptide-vaccinated patients with hepatocellular carcinoma. Top Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. The contents of the Natureevents Directory are now live. The digital version is available here. Find the latest scientific conferences, courses, meetings and symposia on natureevents.com. For event advertising opportunities across the Nature Publishing Group portfolio please contact natureevents@nature.com More Nature Events

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